Carbon tetrachloride poisoning results in sequential disturbances in the function, composition and structure of cytoplasmic organelles of liver parenchymal cells. Other hepatotoxins with similar reactivity in free radical reactions, usually other halocarbons, produce similar lesions. While it is known that carbon tetrachloride is metabolized, it is not yet understood whether it is injurious because its metabolites catalyze an uncontrolled free radical reaction within the cellular membranes, or whether specific products of its metabolism act as antimetabolites. It is proposed to examine the sequential morphologic, enzymatic and compositional changes in cellular membrane systems in cells following poisoning, to determine their cause and interrelationships, and to determine the degree to which cellular functions can be preserved or restored, and cell survival prolonged. By comparing the effects of carbon tetrachloride with those of other agents, the presence or absence of common molecular pathways of injury and responses of cells to injury will be determined. The basis of action of chemical agents which enhance or protect cells against carbon tetrachloride and other haloalkanes will be examined. These agents will include phenobarbital, ethanol, insecticides and polycyclic hydrocarbons, on the one hand, and antioxidants, glutathione and substituted phenothiazines, on the other. The proposed researches will provide a better understanding of the chemical and morphologic events associated with cellular injury, the molecular events responsible and how these events can be detected, prevented or reversed in man.